The objectives of this proposed research are to make creative contributions to the total synthesis of naturally occurring substances possessing clinically significant biological activity. This grant will continue to address the development of new stereoselective reactions and the application of this methodology to the asymmetric synthesis of polyacetate and polypropionate-derived antibiotics and antineoplastic agents. The synthesis targets will include the antineoplastic marine natural products bryostatin, neristatin, miyakolide, spongistatin, and altohyrtin. Polypropionate-derived macrolide antibiotics that will be synthesized include oleandomycin and lankamycin. The methodological studies dealing with new reaction discovery will emphasize the development of reactions for controlling and ultimately predicting the stereochemical course of complex aldol processes. The goal of these studies will be to reveal some of the general rules for predicting the stereochemical outcome of complex aldol fragment coupling reactions.